21-44288472-C-T

Variant names:

• chr21-44288472-C-T
• rs41277546
• NM_000383.4:c.652+14C>T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000383.4(AIRE):​c.652+14C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0157 in 1,561,414 control chromosomes in the GnomAD database, including 262 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.012 (24 hom., cov: 33)
  • Exomes 𝑓: 0.016 (238 hom.)
• Consequence: AIRE NM_000383.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -2.97

Genes affected

AIRE (HGNC:360): (autoimmune regulator) This gene encodes a transcriptional regulator that forms nuclear bodies and interacts with the transcriptional coactivator CREB binding protein. The encoded protein plays an important role in immunity by regulating the expression of autoantigens and negative selection of autoreactive T-cells in the thymus. Mutations in this gene cause the rare autosomal-recessive systemic autoimmune disease termed autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy (APECED). [provided by RefSeq, Jun 2012]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 21-44288472-C-T is Benign according to our data. Variant chr21-44288472-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 35667.We mark this variant Likely_benign, oryginal submissions are: {Benign=5, Uncertain_significance=1}. Variant chr21-44288472-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0123 (1872/152272) while in subpopulation NFE AF= 0.0199 (1350/68006). AF 95% confidence interval is 0.019. There are 24 homozygotes in gnomad4. There are 853 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 24 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AIRE	NM_000383.4	c.652+14C>T		intron_variant	Intron 5 of 13	ENST00000291582.6	NP_000374.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AIRE	ENST00000291582.6	c.652+14C>T		intron_variant	Intron 5 of 13	1	NM_000383.4	ENSP00000291582.5
AIRE	ENST00000530812.5	n.1218C>T		non_coding_transcript_exon_variant	Exon 4 of 12	2
AIRE	ENST00000527919.5	n.1196+14C>T		intron_variant	Intron 4 of 13	2

Frequencies

GnomAD3 genomes AF: 0.0123 AC: 1875 AN: 152154 Hom.: 24 Cov.: 33

Gnomad AFR AF: 0.00314

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.0127

Gnomad ASJ AF: 0.0225

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00436

Gnomad FIN AF: 0.00245

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0199

Gnomad OTH AF: 0.0186

GnomAD3 exomes AF: 0.0131 AC: 3247 AN: 247102 Hom.: 35 AF XY: 0.0134 AC XY: 1797 AN XY: 134178

Gnomad AFR exome AF: 0.00313

Gnomad AMR exome AF: 0.0108

Gnomad ASJ exome AF: 0.0215

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00649

Gnomad FIN exome AF: 0.00298

Gnomad NFE exome AF: 0.0204

Gnomad OTH exome AF: 0.0158

GnomAD4 exome AF: 0.0160 AC: 22588 AN: 1409142 Hom.: 238 Cov.: 27 AF XY: 0.0159 AC XY: 11203 AN XY: 703036

Gnomad4 AFR exome AF: 0.00299

Gnomad4 AMR exome AF: 0.0108

Gnomad4 ASJ exome AF: 0.0218

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00617

Gnomad4 FIN exome AF: 0.00404

Gnomad4 NFE exome AF: 0.0184

Gnomad4 OTH exome AF: 0.0154

GnomAD4 genome AF: 0.0123 AC: 1872 AN: 152272 Hom.: 24 Cov.: 33 AF XY: 0.0115 AC XY: 853 AN XY: 74454

Gnomad4 AFR AF: 0.00313

Gnomad4 AMR AF: 0.0126

Gnomad4 ASJ AF: 0.0225

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00436

Gnomad4 FIN AF: 0.00245

Gnomad4 NFE AF: 0.0199

Gnomad4 OTH AF: 0.0184

Alfa AF: 0.0159 Hom.: 4

Bravo AF: 0.0124

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 27884173) -

Mar 12, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

AIRE: BS1, BS2 -

Polyglandular autoimmune syndrome, type 1 Uncertain:1 Benign:1

Aug 18, 2011

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing;curation

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Mar 15, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.91
DANN	Benign	0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs41277546; hg19: chr21-45708355;